Mesenchymal Stem Cells in Cancer Therapy

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Journal of Genomics. Global reach, higher impact. J Cancer ; 9 17 With the development of cancer treatments, it has become a popular research focus that mesenchymal stem or stromal cells MSCs have the functional mechanisms that influence cancer progression. One of the underestimated mechanisms is secretion of highly specialized double-membrane structures called exosomes. Mesenchymal stem cells generate several exosomes that may act as paracrine mediators by exchanging genetic information.

MSC-derived exosomes are microvesicles ranging from approximately nm in size and detected in various body fluids. It has been demonstrated that MSC-derived exosomes are involved in tumor growth, angiogenesis, metastasis, and invasion. Furthermore, emerging evidence suggests that as natural nanocarriers, MSC-exosomes are responsible for multidrug resistance mechanisms, reverse effect of radiation injury, and immune regulation, which can be used in clinical applications for cancer therapy.

The present review aims to briefly describe the properties and biological functions of MSC-exosomes in cancer progression and its possible clinical applications in the future. Mesenchymal stem or stromal cells MSCs have emerged as a potential solution for tissue repair and wound healing [ 1 ]. Recent data imply that MSCs mediate their therapeutic functions in a paracrine rather than a cellular manner [ 2 ]. At present, the only human cell type known to have a scalable capacity to mass produce exosomes is MSC and MSC is the ideal cell candidate for the mass production of exosomes for drug delivery [ 3 ].

Exosomes, like the intraluminal vesicles, range approximately from nm in diameter secreted by live cells and were first observed in the early s[ 14 ]. Exosomes have been found in numerous body fluids, including blood, amniotic fluid, urine, malignant ascites, cerebrospinal fluid, breast milk, saliva, lymph, and bile, under both healthy and morbid conditions [ 15 - 17 ].

Exosomes have an extracellular membrane vesicle structure composed of a phospholipid bilayer membrane [ 18 ]. Recent information from different cell type reveals that exosomes contain4, proteins, lipids, microRNA and mRNA [ 19 , 20 ]. Also, a multitude of pathways can be activated by exosomes because of cellular interactions with exosomal molecules, including mRNAs, miRNAs, and proteins e. Generally, exosome biogenesis is composed of two steps, the inward budding of membranous vesicles of endosomes and their release into a structure known as a multivesicular body MVB , while exosomes are mainly secreted by two different mechanisms, constitutive release via the Trans-Golgi network and inducible release [ 14 ].

Exosomes interact with target cells, including receptors, endocytosis, fusion with plasma membrane or the release of their cargo [ 22 ]. An additional figure file shows this in more detail Figure 1. In this way, exosomes function as natural nanocarriers, allowing the transport of the bioactive factors they carry to a recipient cell [ 23 ]. Remarkably, MSC-derived exosomes can reach to most tumor territories and provide a suitable microenvironment for cancer development, such as cell proliferation, drug resistance, angiogenesis and metastasis, immune modulation.

Here we will summarize recent studies on the role of MSC-derived exosomes play in cancer development, the mechanism that MSC-exosomes transport cancer drug resistance, and discuss their application to diagnostics and therapy. Mesenchymal Stem Cell-derived Exosomes. At present, MSCs are known as the only human cell type to have a scalable capacity to mass produce exosomes [ 24 ]. The characterization of exosomes has also been found to correlate with its cell origin. Hence, identifying the source of exosomes and isolating them from extracellular matrix through their unique features could be a way to approach.

Under transmission electron microscope, the MSC-derived exosomes still exhibited the characteristic round morphology with heterogeneous size. And the average size of MSC-exosomes was In addition, Nakamura Y et al. Furthermore, Lai R et al. All these studies show how special the exosomes are; their unique features make them a vital component of cancer procession, it is possible that changing the phenotype of MSC-exosomes then they can combine with designated receptor cells and exert specific effects. The number of detected exosomes in patients diagnosed with cancer was found to be increased compared to healthy controls.

Introduction

This finding indicated the significant role of exosomes in the development and progression of various types of cancer [ 34 ]. Growing evidence suggests that MSC-exosomes could transfer proteins, messenger RNA, and microRNA to recipient cells then exert various effects on the growth, metastasis, and drug response of different tumor cells [ 35 ].

And previous studies have demonstrated that mesenchymal stem cells generate several exosomes that may act as paracrine mediators by exchanging genetic information [ 36 , 37 ]. Therefore, understanding the underlying and complex MSC-exosome mediating mechanisms between the tumor cell and their microenvironment in cancer progression is critical to discover the novel therapeutic approach to cancer. MSC-derived exosomes, as paracrine factors, transfer their contents to neighboring tumor cells or induce the phenotypic modifications in recipient cells [ 38 ], which could influence tumor progression in vitro and in vivo.

Furthermore, Qi et al. Yang et al. MSC-exosomes also act as carriers that transport tumor supportive proteins, miRNA, lipids, and metabolites, which plays an essential role in supporting breast cancer growth [ 43 ]. On the contrary, MSC-exosomes can also significantly down-regulated the expression of vascular endothelial growth factor VEGF in breast cancer cells, in vitro and in vivo, which is responsible for the anti-angiogenic effect of MSC-derived exosomes, and suppress the tumor growth in breast cancer [ 44 ].

Another study indicated that MSCs packaged miRb into secreted exosomes, then MSC exosomes carrying miRb delivered the miRNA into glioma cells, which means MSC-exosomes could be used as a vehicle to transfer anti-tumor miRNAs miRb [ 46 ], and reduce glioma xenograft growth in a rat model of primary brain tumor [ 47 ].

Taken together, MSC-exosomes can affect tumor growth in both support and inhibition ways, which depends on the paracrine functions of MSC. It is possible that variable timing of MSC growth, composition of culture media, and passages of MSC used lead to different exosomes then represent the conflicting data [ 48 , 49 ]. Therefore, it is necessary to control growth condition of MSC and make sure they could obtain consistent results with their exosomes. There have been studies on the role of MSC-exosomes in angiogenesis, the cancer cells derived from the exosomes contain interleukin-6 IL-6 and potent pro-angiogenic factors, vascular endothelial growth factor VEGF , other molecules able to enhance organization and endothelial cell in tubule-like structures[ 50 , 51 ].

Many studies have shown that MSCs plays an important role in angiogenesis, but the role of MSC-exosomes in angiogenesis is still controversial, and other studies have suggested that the external secretion of the body has been produced by blood vessels. To analyze the effects of MSC-exosomes on angiogenic activity in vitro, it significant stimulation of angiogenesis to prevent tumor necrosis.

Continuous ROS reactive oxygen species production promotes pathological angiogenesis operating mainly on the VEGF signaling pathway [ 53 ]. In the tumor, tumor mass and stromal cells produce substantial amounts of ROS, and the endogenous ROS production by the tumor cells regulates angiogenesis [ 54 ]. Although the high concentration of MSC-exosomes effectively suppressed tumor growth and angiogenesis, in the beginning, anti-tumor effects of MSC-exosomes were not weakened over time. Thus, MSC-derived exosomes can be an effective anti-angiogenetic agent for anti-tumor therapy.

Tumor metastasis and invasion require formation of a favorable niche, which is a specific microenvironment that promotes tumor cell viability, proliferation, metastasis and invasion [ 55 ]. Several studies have examined the role of MSC-derived exosomes in metastasis, invasion and the formation of a pre-metastatic niche.

And this is the first report about MSC-exosomes promote tumor migration. A year after that, Wang et al. After delving, they found the expression of miR was significantly higher than other miRNA contents existed in GC-MSC-exosomes, and it's known that high expression of miR showed a significant correlation with advanced tumor-node-metastasis stage, local invasion and lymphatic metastasis [ 58 ]. This present study indicates that MSC-exosome elicited this facilitation of migration and invasion in gastric cancer predominantly via the activation of the protein kinase B signaling pathway [ 59 ].

These delivered miR and miR mimics significantly decreased the migration of glioma cells because they decreased the luciferase activity of their respected reporter target genes SCP-1 and Sox2 [ 61 ]. Exosomes could also transfer extracellular miR produced by MSC to osteosarcoma cells, which significantly reduced the migration of osteosarcoma cells [ 62 ].

In breast cancer, increased miRb and decreased MARCKS expression in exosomes secreted by bone marrow mesenchymal stem cells BM-MSCs contribute to cell cycle suppression and dormancy in breast cancer cells, which is one of the mechanisms result in inhibition of migration and invasion in breast cancer [ 63 , 64 ]. To sum up, these results reveal that the MSC-exosomes can have different effects on same cancer, highlighting the necessity of tracking down the mechanism of MSC-exosomes in various tumor cell types. An additional figure file shows this totally [see Figure 2 ].

MSC-Exosome interact with tumor cells. MSC-exosomes could transfer proteins, messenger RNA, and microRNA to recipient tumor cells then exert various effects on the growth, metastasis, and drug response of different tumor cells. Exosomes are considered to be natural nanocarriers which have the absolute predominance in biocompatibility that can be used in clinical applications, such as drug delivery or transfer some specific mRNAs, regulatory miRNAs, lipids, and proteins [ 65 , 66 ].

Their role in cell-to-cell communication and because exogenous cargo can be loaded into them to deliver therapeutics to tumor sites [ 67 , 68 ] provides therapeutic potential for cancer in future clinical medicine. For example, extracted exosomes from BM-MSCs transfected with miR oligonucleotides can act as high-efficiency nanocarriers, which can provide sufficient miR oligonucleotides to influence the tumor microenvironment and tumor aggressiveness effectively and promote oncogenic activity in gastric cancer [ 69 ].

And the delivery of miR by GA-hMSCs-derived exosomes resulted in the down-regulation of the tumor-suppressor NCOR1 in the recipient GSCs, which increase the tumorigenicity of glioma stem-like cells and enhance the aggressiveness of glioblastoma [ 70 ]. On the other hand, due to their membrane composition and the adhesive proteins embedded within them, MSC-exosomes are perfect drug delivery vehicles, to deliver therapeutic agents such as therapeutic miRNA and anti-cancer agents [ 68 ].

A research shows that MSCs are able to package and deliver active drugs through their exosomes, this effect was tested on the human pancreatic cell line CFPAC-1, after priming with Paclitaxel PTX MSCs can acquire strong anti-tumor activity and release the drug through exosomes, verified the possibility of using MSC-exosomes as a carrier to develop drugs with a higher cell-target specificity [ 71 ].

Sometimes, after radiotherapy, chemotherapy, and surgery, the continued presence of small amounts of resistant cancer cells can lead to cancer recurrence. To change the number of untreated cancer cells, the residual tumor cells transfer resistance to sensitive cells through exosomes [ 72 ].

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Exosomes from MSC derived from rat bone marrow can protect the rat pheochromocytoma PC12 cells against the excitotoxicity induced by glutamate [ 35 ]. It was discovered through this experiment that MSCs-exosomes reduced the expression of Bax and Bcl Unfortunately, the lack of robust quantification and widespread adoption of standardized methodologies with high sensitivity and resolution has made accurate comparisons across studies difficult, which has significantly impeded progress i.

S tem C ells T ranslational M edicine ;1— Among the most promising of these engineered cell platforms are mesenchymal stem cells MSCs. However, it should be noted this definition leaves room for significant phenotypic diversity, and these minimal criteria clearly define a heterogeneous population of cells with implications for clinical development 1. Despite this heterogeneity, MSCs have numerous advantages that potentiate their clinical translation.

Although initial trials were premised on the ability of MSCs to repair damaged tissue via cell replacement, more recent clinical development has focused on their potent paracrine and immune regulatory functions 2. These efforts have culminated in more than 1, completed or ongoing clinical trials using MSCs across many disorders with varying degrees of success. The clinical benefits of repurposing MSCs for the treatment of diverse clinical indications are challenged by evolving techniques to improve cell function, localization, and tracking following systemic infusion.

A significant limitation for many of these strategies has been the lack of robust MSC homing to target tissues 6.

The breadth of these factors necessitates that we focus this review on passive homing mechanisms related to cell size and mechanical entrapment, whereas others have recently been reviewed elsewhere A central limitation in evaluating and improving MSC homing has been a lack of robust quantification and widespread adoption of standardized methodologies with high sensitivity and resolution across models and disease states.

The mechanisms for cellular trafficking via systemic circulation were first characterized for leukocyte homing to sites of inflammation, which involves a multistep adhesion and extravasation cascade. Given the role of MSCs in regulating the overall immune response 14 - 16 , it is unsurprising that MSCs are thought to use similar mechanisms to migrate toward inflammatory cues emanating from sites of tissue damage including the tumor microenvironment 13 , 17 - Nitzsche et al. Despite evidence that MSC homing is mediated by specific receptor—ligand pairs, passive entrapment of MSCs in the tumor or sites of injury occurs at least partially as a result of increased vascular permeability and mechanical entrapment in these microenvironments.

An important distinction between MSCs and lymphocytes is their size Fig. It is often unappreciated that relatively small increases in cell diameter translate into significant increases in cell volume, because this value increases as the cube of the radius. This larger cell size, particularly following ex vivo culture 23 , leads to passive arrest of MSCs in small diameter vessels such as terminal arterioles, capillaries, and postcapillary venules as a result of mechanical entrapment. Indeed, the vast majority of MSCs infused intravenously IV are rapidly cleared from the blood and found within the capillary beds of the lungs within minutes of injection 24 - In both humans and animal models, this rapid entrapment is followed by clearance from the lungs and accumulation in the liver and spleen over subsequent hours to days 24 - Similar to lymphocytes, MSCs are thought to increase in size once activated mimicked during ex vivo culture within sites of inflammation and tissue damage.

Although cellular deformability can facilitate passage of larger cells through smaller vessels to some degree 23 , 31 , there is a physical limit to this property that is necessary to maintain cell viability and prevent vessel occlusion. However, mechanical entrapment may still be a dominant driver of MSC biodistribution Fig. To date, there have been limited studies addressing the relative importance of active versus passive arrest in the lungs or other tissues; however, it is likely that both mechanisms are important and can be manipulated to increase homing efficiency to sites of interest.

In our own studies, we have identified MSCs in benign and malignant human prostate tissue These observations led us to initiate studies characterizing MSC biodistribution, kinetics, and trafficking toward different prostate cancer xenografts postinfusion, in addition to assessing chemokine and cognate receptor profiles to identify key pathways mediating MSC tumor tropism in prostate cancer.

IV: 0. Autoradiography confirmed tissue distribution of infiltrating MSCs with tumor localization restricted to the periphery as expected based on the vascular pattern of subcutaneous tumors Fig. To partially overcome this barrier and improve targeting, preadministration of vasodilators such as sodium nitroprusside have been used to reduce lung entrapment in mouse models 21 , In addition, multiple investigators have developed ex vivo expansion protocols reported to generate MSC cultures with smaller average cell diameters 34 - Recently, Luo et al.

Methods to track MSCs have largely been variations of the same core techniques, each with advantages and disadvantages Table 2. Of these approaches, ex vivo histological analysis is the most common. This is typically performed using MSCs labeled with a fluorescent lipophilic vital dye e. T2 hypointensity indistinguishablefrom tumor hemorrhage;False positives due to macrophage uptake;2D image; Label diluted with each cell division; Potential cytotoxicity and ROS generation; Sophisticated equipment and expertise needed.

Imaging in context of natural microenvironment;Visualization of dynamic processes migration, vascular adhesion, TEM. Enumeration of circulating cells; Tracking dynamic entry and exit from circulation; Detection of cell flow velocities;Analysis of large blood volume; No artifacts from cell isolation and processing. This methodology can accurately quantify rare transcripts in the range of 0. However, BLI and fluorescence have limited translational application, and for BLI, the signal is dependent on vascular delivery of the luciferase substrate.

Consequently, the signal is not necessarily proportional to MSC homing and is highly sensitive to vascular disrupting agents. In addition, both BLI and fluorescent signals have a limited depth of tissue penetration, meaning that signal quantification is not directly comparable for tissues at different depths. Fluorescence imaging with cell labeling dyes has been widely used in the small animal imaging field to track the distribution of cells labeled ex vivo with membrane binding dyes.

Light propagation through tissue is heavily dependent on wavelength, and redshifted or near infrared dyes enable visualization of labeled cells through several millimeters of tissue. DeGrado et al. Another intriguing approach has been to engineer MSCs to express the sodium iodide symporter NIS , which can be exploited for imaging I or therapeutic I applications 48 , It should be noted that many unbound radionuclides inherently accumulate in the bone and liver when released into systemic circulation. Despite the multitudes of advantages that cell therapy provides they are limited in three main domains 1 Low cell retention and survival at the site of the tumor 2 In ability to co-deliver multiple therapeutics and 3 In ability to deliver drugs other than peptide based drugs.

This thesis details the work to engineer mesenchymal stem cells to tackle these three issues and develop a system that can increase the efficacy of glioblastoma treatment. To increase the cellular retention and survival we engineered MSC to form multicellular spheroids and cell sheets. The system showed superior performance due to the increased retention of the cells and nanoparticle at the tumor site.

Finally, to deliver drugs other peptide based we engineered graphene oxide cellular patches for mesenchymal stem cells. Graphene oxide can carry diverse therapeutics and can kill the cancer cells without affecting the cellular viability of MSC. Columbia University Libraries. Academic Commons.